Ponvory
ponesimod
Species
RatMouseDogRabbit
Longest study
52 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog (mouse for carcinogenicity, rabbit for EFD)
“The pivotal nonclinical studies were conducted in CD-1 mouse, Wistar rat, beagle dog, and New Zealand White rabbit.”
Why that species
Rat considered pharmacologically relevant despite 5-fold lower S1P3 potency than human
“In in vitro PD studies ACT-128800 was found to have a 5-fold reduced potency on rat S1P3 receptor as compared to the human counterpart. Nevertheless, the rat is considered a relevant species for the evaluation of the safety of ACT-128800.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In rat, oral administration of ponesimod (0, 3, 10, or 30 mg/kg/day in males and 0, 10, 30, or 100 mg/kg/day in females) did not result in an increase in tumors.”
Study lengthopen answer page →
Longest pivotal study
52 (52-week dog)
“Study title: ACT-128800: 52-Week Follow-up Oral (Gavage) Toxicity Study in the Beagle Dog”
Pivotal GLP studies
26-week rat and 26- and 52-week dog oral studies
“After chronic treatment for 26 weeks, NOAELs for systemic toxicity were established at 30 mg/kg/day in rats and at 2 mg/kg/day in dogs. In the 52-week toxicity study in dogs, the applicant derived a NOAEL at 3 mg/kg/day.”
Route in tox
Oral (gavage)
“Route of administration: Oral by gavage”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and rat micronucleus assays
“Ponesimod was negative in in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (micronucleus in rat) assays.”
Carcinogenicity
2-year rat: no drug-related tumors; mouse: hemangiomas/hemangiosarcomas at all doses in males and high-dose females
“In the 2-year rat carcinogenicity study, there were no drug-related increases in neoplasms in M or F. The mouse study was positive for hemangiomas and hemangiosarcomas, with an increase in incidences at all doses in M and in HDF.”
Reproductive & developmental
Fertility unaffected in rats (NOAEL 100 mg/kg/day); rat and rabbit EFD: teratogenicity and fetal lethality
“In the reproductive and development studies with oral ponesimod, fertility was not affected in F or M (NOAEL was 100 mg/kg/day), but teratogenicity and fetal lethality was observed in both rats and rabbits.”
Safety pharmacology
Single dose decreased heart rate and blood pressure and caused first- to third-degree AV block in guinea pigs
“In cardiovascular safety pharmacology studies, a single oral dose of ponesimod decreased heart rate, blood pressure, and caused first-, second-, and third-degree AV block in guinea pigs.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Ponvory don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Lung toxicity NOAELs: 90/30 mg/kg (male/female mouse), 4 mg/kg (rat), 3 mg/kg (dog) (FDA pharmacology/toxicology review, p. 11)
NOAEL / key findings
Lung toxicity NOAELs: 90/30 mg/kg (male/female mouse), 4 mg/kg (rat), 3 mg/kg (dog)
“The NOAELs for lung toxicity were 90 and 30 mg/kg in M and F mice, respectively, 4 mg/kg in rats, and 3 mg/kg in dogs.”
Risksopen answer page →
Immune & cytokine safety
Reversible suppression of T-cell dependent antibody response during dosing
“The TDAR results suggest that there is immune suppression during the dosing of ponesimod that recovers when dosing is stopped.”
Biodistribution & persistence
Wide tissue distribution; highest in GI tract and liver; brain and spinal cord above blood levels
“In albino rats, radioactivity was widely distributed into most tissues and was maximal at 1-4 hours post-dose. The highest exposures were found in GI tract and liver but was also observed in the brain and spinal cord at higher levels than blood at 1-4 hours post-dose.”
Modality-specific risk
Cardiovascular and lung toxicity, and serious teratogenic effects
“The pivotal nonclinical studies of ponesimod were adequately conducted and identified target organs for toxicity (including cardiovascular and lung) and serious developmental (teratogenic) effects.”